ENZASTAURIN

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C32H29N5O2
Molecular Weight	515.6062
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cn1cc(c2ccccc21)C3=C(c4cn(C5CCN(CC5)Cc6ccccn6)c7ccccc47)C(=O)N=C3O

InChI

InChIKey=AXRCEOKUDYDWLF-UHFFFAOYSA-N

InChI=1S/C32H29N5O2/c1-35-19-25(23-9-2-4-11-27(23)35)29-30(32(39)34-31(29)38)26-20-37(28-12-5-3-10-24(26)28)22-13-16-36(17-14-22)18-21-8-6-7-15-33-21/h2-12,15,19-20,22H,13-14,16-18H2,1H3,(H,34,38,39)

HIDE SMILES / InChI

Molecular Formula	C32H29N5O2
Molecular Weight	515.6062
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/22879385 | https://www.ncbi.nlm.nih.gov/pubmed/16103100 | https://investor.lilly.com/releasedetail.cfm?ReleaseID=763858 | https://www.ncbi.nlm.nih.gov/pubmed/28325267

Enzastaurin is a serine/threonine kinase inhibitor that showed antiangiogenic, antiproliferative, and proapoptotic properties in vitro and antitumor activity in vivo in a xenograft Waldenström macroglobulinemia (WM) model. Enzastaurin (LY317615) is a potent PKCβ selective inhibitor. Enzastaurin suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis. Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. Eli Lilly discontinued development of enzastaurin after top-line data from the double-blind, international Phase III PRELUDE trial in 758 DLBCL patients showed that enzastaurin missed the primary endpoint of improving DFS vs. placebo.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Protein kinase C beta 20 Target ID: CHEMBL3045 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16103100 \| https://www.ncbi.nlm.nih.gov/pubmed/12749884	Inhibitor 7728		6.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Waldenström's macroglobulinemia 7 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22879385	Primary	Phase II 1101	Unknown Approved Use Unknown
Diffuse large B-cell lymphoma 20 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28325267 https://clinicaltrials.gov/ct2/show/NCT00332202	Primary	Phase III 643	Unknown Approved Use Unknown
Glioblastoma 55 Sources: https://clinicaltrials.gov/ct2/show/NCT00295815 https://www.ncbi.nlm.nih.gov/pubmed/21896554 https://www.ncbi.nlm.nih.gov/pubmed/20124186	Primary	Phase III 643	Unknown Approved Use Unknown

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1601	inhibitor 1604

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP19A1 56 CYP2C8 818 P-gp 1330 BCRP 643 CYP2C19 1325 CYP3A 191	CYP3A 172

Drug as perpetrator

Target	Modality	Activity
P-gp 1514	inhibitor 3045 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=377020422	inconclusive [IC50 29.0929 uM]
CYP19A1 56	inhibitor 3045 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/743139#sid=144206918	no
BCRP 713	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/25749379/	yes
CYP2C19 1392	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/19955926/	yes
CYP2C8 865	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/19955926/	yes
CYP2C9 1648	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/19955926/	yes
CYP3A 271	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/19955926/	yes
P-gp 1514	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/25749379/	yes

Drug as victim

Target	Modality	Activity	Metabolite
CYP3A 172	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/16943527/	yes
CYP3A 172	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/16943527/	yes	LY326020 4
CYP3A4 1601	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/19955926/	yes

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY100444	https://www.001chemical.com/chem/search?q=DY100444
1PlusChem LLC	1P00AC0J	https://www.1pchem.com/search?query=1P00AC0J
A2B Chem	AE81331	http://a2bchem.com/prod/AE81331
AChemBlock	M15420	http://www.achemblock.com/catalogsearch/result/?q=M15420
AK Scientific	W3715	https://aksci.com/item_detail.php?cat=W3715
Alfa Chemistry	ACM359017791	http://www.alfa-chemistry.com/search.aspx?q=ACM359017791
ApexBio Technology	A1670	https://www.apexbt.com/catalogsearch/result/?q=A1670
AstaTech	43222	http://astatechinc.com/CPSResult.php?CRNO=43222
Axon MedChem	1682	https://www.axonmedchem.com/product/1682
BOC Sciences	170364-57-5	http://www.bocsci.com/description.asp?cas=170364-57-5
Capot Chemical	24445	https://www.capotchem.com/search.do?q=24445
Cayman Chemical	11601	http://www.caymanchem.com/app/template/Product.vm/catalog/11601
Chem Scene	CS-0132	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0132
ChemShuttle	104790	https://www.chemshuttle.com/catalogsearch/result/?q=104790
Excenen	EX-A1055	http://www.excenen.com/searchresultlist.php?id=EX-A1055
Exclusive Chemistry	2315	http://www.exchemistry.com/chem-catalog/product-2315.html
KeyOrganics	LE-0014	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=LE-0014
KeyOrganics	LE-0020	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=LE-0020
Lab Seeker	SC-85687	http://www.labseeker.com/search.php?keywords=SC-85687&category=0
LabSeeker	SC-85687	http://www.labseeker.com/search.php?keywords=SC-85687&category=0
Matrix Scientific	90588	http://www.matrixscientific.com/090588.html
MedChem Express	HY-10342	https://www.medchemexpress.com/search.html?q=HY-10342&ft=&fa=&fp=
MolPort	MolPort-009-194-230	https://www.molport.com/shop/molecule-link/MolPort-009-194-230
Molcore	MC100444	http://www.molcore.com/CatMC100444.html
Molnova	M12602	https://www.molnova.com/en/serch-list.html?keywords=M12602
MuseChem	I002225	https://www.musechem.com/product/I002225.html
PI Chemicals	PI-38650	http://www.pipharm.com/catalog_products/PI-38650.html
Selleck Chemicals	S1055	http://www.selleckchem.com/search.html?searchDTO.searchParam=S1055
ShangHai Biochempartner	BCP000445	http://www.biochempartner.com/search_BCP000445
ShangHai Biochempartner	BCP02703	http://www.biochempartner.com/search_BCP02703
TargetMol	T6280	https://www.targetmol.com/search?keyword=T6280
Toronto Research Chemicals	A172117	https://www.trc-canada.com/product-detail/?CatNum=A172117
Toronto Research Chemicals	E560000	https://www.trc-canada.com/product-detail/?CatNum=E560000
W&J PharmaChem	50C936862	http://wjpharmachem.com/new/searcht.php?keyword=50C936862
eMolecules	31225824	https://orderbb.emolecules.com/search/#?query=31225824
eMolecules	36745713	https://orderbb.emolecules.com/search/#?query=36745713
eNovation Chemicals	K31327	https://www.enovationchem.com/Products.asp?SEARCHTEXT=K31327&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-9959734001	https://mcule.com/MCULE-9959734001/

PubMed

Title	Date	PubMed
Reduction of HLA-DR+ lymphocytes after treatment with enzastaurin in patients with metastatic thyroid cancer.	2008	18667816
Enzastaurin, an inhibitor of PKCbeta, Enhances Antiangiogenic Effects and Cytotoxicity of Radiation against Endothelial Cells.	2008 Dec	19043530
Exploring multi-targeting strategies for the treatment of gliomas.	2008 Dec	19037835
Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells.	2008 Dec 2	19034280
Targeted treatment and new agents in diffuse large B-cell lymphoma.	2008 Jul	18760704
[Protein kinases C: a new cytoplasmic target].	2008 Jul-Aug	18755647
[Recent therapeutic progress in non-Hodgkin lymphoma: focusing on diffuse large B-cell lymphoma and follicular lymphoma].	2008 Oct	18833928
Protein kinase C beta in malignant pleural mesothelioma.	2008 Oct	18765998
Novel therapies in breast cancer: what is new from ASCO 2008.	2008 Oct 1	18828924
Advances in the treatment of monoclonal gammopaties: The emerging role of targeted therapy in plasma cell dyscrasias.	2008 Sep	19707373
Molecular pathways involved in the synergistic interaction of the PKC beta inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells.	2008 Sep 2	18728666
MET/PKCbeta expression correlate with metastasis and inhibition is synergistic in lung cancer.	2009	19955662
Current available therapies and future directions in the treatment of malignant gliomas.	2009	19707392
In Vivo Measurements of Tumor Metabolism and Growth after Administration of Enzastaurin Using Small Animal FDG Positron Emission Tomography.	2009	19503801
Design of Phase II cancer trials for evaluation of cytostatic/cytotoxic agents.	2009	19384693
Role of PKCbeta in hepatocellular carcinoma cells migration and invasion in vitro: a potential therapeutic target.	2009	19112601
Perspectives of protein kinase C (PKC) inhibitors as anti-cancer agents.	2009 Apr	19356127
Synergistic anti-tumor efficacy of lovastatin and protein kinase C-beta inhibitor in hepatocellular carcinoma.	2009 Aug	19096848
Combination of enzastaurin and pemetrexed inhibits cell growth and induces apoptosis of chemoresistant ovarian cancer cells regulating extracellular signal-regulated kinase 1/2 phosphorylation.	2009 Aug 18	19701501
Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents.	2009 Dec	20044633
Carboplatin and paclitaxel in combination with oral enzastaurin in advanced ovarian or primary peritoneal cancer: results from a safety lead-in study.	2009 Dec	19955926
A phase II study of oral enzastaurin in patients with metastatic breast cancer previously treated with an anthracycline and a taxane containing regimen.	2009 Dec	19214387
Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling.	2009 Feb 12	19018094
Protein kinase Cbeta is an effective target for chemoprevention of colon cancer.	2009 Feb 15	19221092
In vivo/ex vivo and in situ assays used in cancer research: a brief review.	2009 Jan	19098118
Antiangiogenic drugs in ovarian cancer.	2009 Jan 13	19002176
Enzastaurin shows preclinical antitumor activity against human transitional cell carcinoma and enhances the activity of gemcitabine.	2009 Jul	19509273
Quantitative in situ detection of phosphoproteins in fixed tissues using quantum dot technology.	2009 Jul	19332430
Protein kinase C-beta II (PKC-beta II) expression in patients with colorectal cancer.	2009 Jun	19277684
Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1alpha-dependent pathway in multiple myeloma.	2009 Jun 15	19509231
Molecular targeting of the PKC-beta inhibitor enzastaurin (LY317615) in multiple myeloma involves a coordinated downregulation of MYC and IRF4 expression.	2009 Mar	18759374
PKCbeta is essential for the development of chronic lymphocytic leukemia in the TCL1 transgenic mouse model: validation of PKCbeta as a therapeutic target in chronic lymphocytic leukemia.	2009 Mar 19	19168795
Overview of current and future biologically based targeted therapies in head and neck squamous cell carcinoma.	2009 Mar 2	19284526
[Role of PKCbeta in the malignant tumors and enzastaurin, a PKCbeta inhibitor].	2009 May	19618717
A phase I trial of enzastaurin in patients with recurrent gliomas.	2009 May 15	19417015
Synergistic effect of Sorafenib and Sunitinib with Enzastaurin, a selective protein kinase C inhibitor in renal cell carcinoma cell lines.	2009 May 18	19171421
Conformationally constrained analogues of diacylglycerol (DAG). 31. Modulation of the biological properties of diacylgycerol lactones (DAG-lactones) containing rigid-rod acyl groups separated from the core lactone by spacer units of different lengths.	2009 May 28	19379015
Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer.	2009 Sep	19487488
Enzastaurin (LY317615), a protein kinase C beta selective inhibitor, enhances antiangiogenic effect of radiation.	2010 Aug 1	19906497
Combined RNA-expression and 2D-PAGE-screening identifies comprehensive interaction networks affected after bortezomib or enzastaurin exposure of mantle cell lymphoma.	2010 Feb 15	20082812
Protein kinase Calpha: disease regulator and therapeutic target.	2010 Jan	19969380
Enzastaurin induces H2AX phosphorylation to regulate apoptosis via MAPK signalling in malignant glioma cells.	2010 Jan	19913408
Synergistic antifibrotic efficacy of statin and protein kinase C inhibitor in hepatic fibrosis.	2010 Jan	19910526
Recruitment of PKC-betaII to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70.	2010 Jan	19907441
Pharmacological aspects of the enzastaurin-pemetrexed combination in non-small cell lung cancer (NSCLC).	2010 Jan	19839931
MicroRNA-21 inhibitor sensitizes human glioblastoma cells U251 (PTEN-mutant) and LN229 (PTEN-wild type) to taxol.	2010 Jan 31	20113523
Protein kinase Cbeta modulates ligand-induced cell surface death receptor accumulation: a mechanistic basis for enzastaurin-death ligand synergy.	2010 Jan 8	19887445
Phase II, double-blinded, randomized study of enzastaurin plus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer.	2010 Mar	20090562
Long-term follow-up of chemonaive patients with asymptomatic metastatic colorectal cancer treated with enzastaurin in a window of opportunity phase II study.	2010 May	19914961
A window of opportunity phase II study of enzastaurin in chemonaive patients with asymptomatic metastatic colorectal cancer.	2010 May	19901015

Patents

Sample Use Guides

In Vivo Use Guide

1125 mg loading dose then 500 mg, oral, daily, until disease progression or maximum of 3 years

Route of Administration: Oral

In Vitro Use Guide

In the BON1 cell line Enzastaurin inhibited cell proliferation at 5 and 10 uM by inducing caspase-mediated apoptosis, and reduced phosphorylation of glycogen synthetase kinase 3β (GSK3β) and of Akt, both downstream targets of PKC pathway and pharmacodynamic markers for Enzastaurin.

Substance Class	Chemical Created by `admin` on `Sat Jun 26 16:00:29 UTC 2021` Edited by `admin` on `Sat Jun 26 16:00:29 UTC 2021`
Record UNII	UC96G28EQF
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ENZASTAURIN

Official Name

English

ENZASTAURIN [MI]

Common Name

English

LY317615

Code

English

ENZASTAURIN [WHO-DD]

Common Name

English

LY-317615

Code

English

3-(1-METHYL-1H-INDOL-3-YL)-4-(1-(1-(PYRIDIN-2-YLMETHYL)PIPERIDIN-4-YL)-1H-INDOL-3-YL)-1H-PYRROLE-2,5-DIONE

Systematic Name

English

ENZASTAURIN [INN]

Common Name

English

1H-PYRROLE-2,5-DIONE, 3-(1-METHYL-1H-INDOL-3-YL)-4-(1-(1-(2-PYRIDINYLMETHYL)-4-PIPERIDINYL)-1H-INDOL-3-YL)-

Systematic Name

English

DB-102

Code

English

ENZASTAURIN [USAN]

Common Name

English

DB102

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

277209